The recognition of ubiquitinated proteins by the proteasome.

The ability of ubiquitin to form up to eight different polyubiquitin chain linkages generates complexity within the ubiquitin proteasome system, and accounts for the diverse roles of ubiquitination within the cell. Understanding how each type of ubiquitin linkage is correctly interpreted by ubiquitin binding proteins provides important insights into the link between chain recognition and cellular fate. A major function of ubiquitination is to signal degradation of intracellular proteins by the 26S proteasome. Lysine-48 (K48) linked polyubiquitin chains are well established as the canonical signal for proteasomal degradation, but recent studies show a role for other ubiquitin linked chains in facilitating degradation by the 26S proteasome. Here, we review how different types of polyubiquitin linkage bind to ubiquitin receptors on the 26S proteasome, how they signal degradation and discuss the implications of ubiquitin chain linkage in regulating protein breakdown by the proteasome.JAN is supported by a Wellcome Trust Senior Clinical Research Fellowship (102770/Z/13/Z). The Cambridge Institute for Medical Research is in receipt of a Wellcome Trust Strategic Award (100140).This is the final published version. It first appeared from Springer via https://doi.org/10.1007/s00018-016-2255-

Novel Cascaded Ultra Bright Pulsed Source of Polarization Entangled Photons

A new ultra bright pulsed source of polarization entangled photons has been realized using type-II phase matching in spontaneous parametric down conversion process in two cascaded crystals. The optical axes of the crystals are aligned in such a way that the extraordinarily (ordinarily) polarized cone from one crystal overlaps with the ordinarily (extraordinarily) polarized cone from the second crystal. This spatial overlapping removes the association between the polarization and the output angle of the photons that exist in a single type-II down conversion process. Hence, entanglement of photons originating from any point on the output cones is possible if a suitable optical delay line is used. This delay line is particularly simple and easy to implement.Comment: 8 pages 8 figure

Reliability of the beamsplitter based Bell-state measurement

A linear 50/50 beamsplitter, together with a coincidence measurement, has been widely used in quantum optical experiments, such as teleportation, dense coding, etc., for interferometrically distinguishing, measuring, or projecting onto one of the four two-photon polarization Bell-states $|\psi^{(-)}>$. In this paper, we demonstrate that the coincidence measurement at the output of a beamsplitter cannot be used as an absolute identifier of the input state $|\psi^{(-)}>$ nor as an indication that the input photons have projected to the $|\psi^{(-)}>$ state.Comment: 4 pages, two-colum

Electrocatalytic CO2 reduction by M(bpy-R)(CO)4 (M = Mo, W; R = H, tBu) complexes. Electrochemical, spectroscopic, and computational studies and comparison with group 7 catalysts

The tetracarbonyl molybdenum and tungsten complexes of 2,2′-bipyridine and 4,4′-di-tert-butyl-2,2′-bipyridine (M(bpy-R)(CO)4; R = H, M = Mo (1), W (2); R = tBu, M = Mo (3), W (4)) are found to be active electrocatalysts for the reduction of CO2. The crystal structures of M(bpy-tBu)(CO)4 (M = Mo (3), W (4)), the singly reduced complex [W(bpy)(CO)4][K(18-crown-6] (5) and the doubly reduced complex [W(bpy-tBu)(CO)3][K(18-crown-6)]2 (6) are reported. DFT calculations have been used to characterize the reduced species from the reduction of W(bpy-tBu)(CO)4 (4). These compounds represent rare examples of group 6 electrocatalysts for CO2 reduction, and comparisons are made with the related group 7 complexes that have been studied extensively for CO2 reduction

Bell State Preparation using Pulsed Non-Degenerate Two-Photon Entanglement

We report a novel Bell state preparation experiment. High-purity Bell states are prepared by using femtosecond pulse pumped \emph{nondegenerate} collinear spontaneous parametric down-conversion. The use of femtosecond pump pulse {\em does not} result in reduction of quantum interference visibility in our scheme in which post-selection of amplitudes and other traditional mechanisms, such as, using thin nonlinear crystals or narrow-band spectral filters are not used. Another distinct feature of this scheme is that the pump, the signal, and the idler wavelengths are all distinguishable, which is very useful for quantum communications.Comment: 4 pages, submitted to PR

Ranking buffel: comparative risk and mitigation costs of key environmental and socio-cultural threats in central Australia

Changed fire regimes and the introduction of rabbits, cats, foxes, and large exotic herbivores have driven widespread ecological catastrophe in Australian arid and semi-arid zones, which encompass over two-thirds of the continent. These threats have caused the highest global mammal extinction rates in the last 200 years, as well as significantly undermining social, economic, and cultural practices of Aboriginal peoples of this region. However, a new and potentially more serious threat is emerging. Buffel grass (Cenchrus ciliaris L.) is a globally significant invader now widespread across central Australia, but the threat this ecological transformer species poses to biodiversity, ecosystem function, and culture has received relatively little attention. Our analyses suggest threats from buffel grass in arid and semi-arid areas of Australia are at least equivalent in magnitude to those posed by invasive animals and possibly higher, because unlike these more recognized threats, buffel has yet to occupy its potential distribution. Buffel infestation also increases the intensity and frequency of wildfires that affect biodiversity, cultural pursuits, and productivity. We compare the logistical and financial challenges of creating and maintaining areas free of buffel for the protection of biodiversity and cultural values, with the creation and maintenance of refuges from introduced mammals or from large-scale fire in natural habitats. The scale and expense of projected buffel management costs highlight the urgent policy, research, and financing initiatives essential to safeguard threatened species, ecosystems, and cultural values of Aboriginal people in central Australia

The Proteasome Distinguishes between Heterotypic and Homotypic Lysine-11-Linked Polyubiquitin Chains.

Proteasome-mediated degradation occurs with proteins principally modified with lysine-48 polyubiquitin chains. Whether the proteasome also can bind atypical ubiquitin chains, including those linked by lysine-11, has not been well established. This is critically important, as lysine-11 polyubiquitination has been implicated in both proteasome-mediated degradation and non-degradative outcomes. Here we demonstrate that pure homotypic lysine-11-linked chains do not bind strongly to the mammalian proteasome. By contrast, heterotypic polyubiquitin chains, containing lysine-11 and lysine-48 linkages, not only bind to the proteasome but also stimulate the proteasomal degradation of the cell-cycle regulator cyclin B1. Thus, while heterotypic lysine-11-linked chains facilitate proteasomal degradation, homotypic lysine-11 linkages adopt conformations that prevent association with the proteasome. Our data demonstrate the capacity of the proteasome to bind ubiquitin chains of distinct topology, with implications for the recognition and diverse biological functions of mixed ubiquitin chains.This work is supported by a Wellcome Trust Senior Clinical Research Fellowship to JAN (102770/Z/13/Z), a Wellcome Trust Fellowship to MPW (093966/Z/10/Z) and a National Institute of Health grant (GM067945) to SPG. The Cambridge Institutefor Medical Research is in receipt of a Wellcome Trust Strategic Award [100140].This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.celrep.2015.06.06

Carbon and sulfur isotopic composition of alkyl- and benzo-thiophenes provides insights into their origins and formation pathways

Thiophenic compounds can provide significant geochemical information and may be used as paleoenvironmental indicators as long as their biological origins and formation pathways are understood. To this end, we investigated the structures, distributions, δ13C and δ34S values, of specific thiophenic compounds extracted from immature sedimentary rocks from the Upper Cretaceous (Ghareb Formation, Shefela Basin, Israel). Isoprenoidal alkylthiophenes (ATs) showed a general trend of depletion in their 13C and 34S values relative to the normal (linear) ATs extracted from the studied samples. In addition, a consistent enrichment of up to 2‰ in 13C and 8‰ in 34S of methylated ATs (m/z = 111), relative to non-methylated ones (m/z = 97), was recorded. This suggests that AT precursors derived from different organisms and diagenetic pathways, which later affected their sulfurization mechanisms. The large variation, of ∼15‰, in the δ34S values of individual ATs, along with the general trend of 13C depletion with increasing Tmax, suggests that ATs formed by a set of diagenetic processes of mild thermochemical alteration. The δ13C values of benzothiophenes (BTs) were enriched in 13C relative to the rest of the organic sulfur compounds; by ∼3‰ on average. This in turn suggests that BTs were generated mainly by sulfurization and subsequent ring closure, or aromatization of 13C-enriched aromatic/alkyl cyclohexane compounds with unsaturation and/or functional groups in their alkyl chain. Such 13C-enriched precursors can be generated from carotenoids and terrestrial compounds (e.g., by lignin degradation). The large variation in δ34S values of individual BTs, of ∼15‰, suggests that the BTs in our samples were formed during diagenesis and did not experience advanced thermal alteration processes. Therefore, their occurrence in immature sedimentary rocks might be used as a proxy for early thermochemical alteration that cannot be detected using conventional geochemical indicators, such as Tmax. The combination of structural, 13C and 34S investigations of individual organic sulfur compounds enhanced an understanding of their sulfurization pathways and origins, which in turn may expand their utilization as paleoenvironmental indicators

Selective Histone Deacetylase 6 Inhibitors Restore Cone Photoreceptor Vision or Outer Segment Morphology in Zebrafish and Mouse Models of Retinal Blindness.

Blindness arising from retinal or macular degeneration results in significant social, health and economic burden. While approved treatments exist for neovascular ('wet') age-related macular degeneration, new therapeutic targets/interventions are needed for the more prevalent atrophic ('dry') form of age-related macular degeneration. Similarly, in inherited retinal diseases, most patients have no access to an effective treatment. Although macular and retinal degenerations are genetically and clinically distinct, common pathological hallmarks can include photoreceptor degeneration, retinal pigment epithelium atrophy, oxidative stress, hypoxia and defective autophagy. Here, we evaluated the potential of selective histone deacetylase 6 inhibitors to preserve retinal morphology or restore vision in zebrafish atp6v0e1 -/- and mouse rd10 models. Histone deacetylase 6 inhibitor, tubastatin A-treated atp6v0e1 -/- zebrafish show marked improvement in photoreceptor outer segment area (44.7%, p = 0.027) and significant improvement in vision (8-fold, p ≤ 0.0001). Tubastatin A-treated rd10/rd10 retinal explants show a significantly (p = 0.016) increased number of outer-segment labeled cone photoreceptors. In vitro, ATP6V0E1 regulated HIF-1α activity, but significant regulation of HIF-1α by histone deacetylase 6 inhibition in the retina was not detected. Proteomic profiling identified ubiquitin-proteasome, phototransduction, metabolism and phagosome as pathways, whose altered expression correlated with histone deacetylase 6 inhibitor mediated restoration of vision

What Should a Psychiatrist Know About Genetics? Review and Recommendations From the Residency Education Committee of the International Society of Psychiatric Genetics.

The International Society of Psychiatric Genetics (ISPG) created a Residency Education Committee with the purpose of identifying key genetic knowledge that should be taught in psychiatric training programs. Thirteen committee members were appointed by the ISPG Board of Directors, based on varied training, expertise, gender, and national origin. The Committee has met quarterly for the past 2 years, with periodic reports to the Board and to the members of the Society. The information summarized includes the existing literature in the field of psychiatric genetics and the output of ongoing large genomics consortia. An outline of clinically relevant areas of genetic knowledge was developed, circulated, and approved. This document was expanded and annotated with appropriate references, and the manuscript was developed. Specific information regarding the contribution of common and rare genetic variants to major psychiatric disorders and treatment response is now available. Current challenges include the following: (1) Genetic testing is recommended in the evaluation of autism and intellectual disability, but its use is limited in current clinical practice. (2) Commercial pharmacogenomic testing is widely available, but its utility has not yet been clearly established. (3) Other methods, such as whole exome and whole genome sequencing, will soon be clinically applicable. The need for informed genetic counseling in psychiatry is greater than ever before, knowledge in the field is rapidly growing, and genetic education should become an integral part of psychiatric training